IL101046A - Substituted imidazotri-azoloquinazoline compounds their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Imidazotriazoloquinazoline compounds having the general formula <IMAGE> wherein A together with the alpha -marked carbon atom and the beta -marked nitrogen atom is one of the groups <IMAGE> <IMAGE> <IMAGE> cyano or CO2R5, wherein R5 is H, alkyl, cycloalkyl, trifluoromethyl or alkoxymethyl; and R2, R3 and R4 independently are H, hydroxy, halogen, CN, alkyl, alkenyl, alkynyl, trifluoromethyl, alkoxy, dialkylaminoalkoxy, aralkoxy, aryloxy which may be substituted, acyclic amino group, or NR6R7, wherein R6 and R7 independently are H or alkyl. The compounds are useful in psychopharmaceutical preparations as anticonvulsants, anxiolytics, hypnotics, antipsychotics, antiemetics, or in improving the cognitive function of the brain of mammals, or as benzodiazepine antagonsists. [US5260298A]

Description

101046/2 Substituted imidazotriazoloquinazoline compounds, their preparation and pharmaceutical compositions containing them NOVO NORDISK A/S C. 85674 1 1046/2 1 The present invention relates to therapeutically active tetracyclic imidazotriazoloquinazoline compounds, a method of preparing the same, pharmaceutical composi- tions comprising the compounds, and to methods of treating therewith. The novel compounds are useful in psycho-pharmaceutical applications, e.g., in the treatment of central nervous system ailments, for example, as anticonvulsants, anxiolytics, hypnotics, antipsychotics, antiemetics, in improving the cognitive function of the brain of mammals, or as benzodiazepine antagonists.

It is well known (Squires, R.F. and Braestrup, C. in Nature (London) 266 (1977) 732-734) that specific sites in the central nervous systems of vertebrates exhibit a high specific affinity for binding 1,4- and 1,5-benzodiazepines . These sites are called benzodiazepine receptors .

It has now been found that members of a novel group of tetracyclic imidazotriazoloquinazoline compounds have strong affinity for the benzodiazepine receptors which make them useful in psychopharmaceutical preparations .

Accordingly, it is an object of the invention to provide such novel tetracyclic imidazotriazoloquinazoline compounds .

The compounds of the invention have the general formula I and pharmaceutically acceptable acid addition salts thereof, wherein A together with the O^-marked carbon atom and the β- marked nitrogen atom is one of the groups wherein R is hydrogen, C.^ ^-alkyl, C^y-cycloalkyl , trifluoromethyl or and 2 3 4 R , R and R independently are hydrogen, hydroxy, halogen, CN, alkyl, C2_g-alkenyl, C2_g-alkynyl, trifluoromethyl, C1_g-alkoxy, dialkylaminoalkoxy, 0 aralkoxy, aryloxy which may be substituted with halogen 6 7 6 or alkoxy, a cyclic amino group, or NR R , wherein R 7 and R independently are hydrogen or ^-alkyl.

The invention also relates to methods of preparing the above mentioned compounds. These methods comprise: a) reacting a compound of formula II (ID wherein A, R and R are as defined above and wherein Y is a leaving group, with a compound having the formula CN - CH„ - R (III) wherein R is as defined above, to form a compound of the invention, or b) reacting a reactive derivative of a compound having the general formula IV wherein A, R and R are as defined above with a compound having the general formula V R -C( =N0H )NH, (V) wherein R is as defined above to form a compound of the general formula I wherein R is wherein R is as defined above, or c) reacting a compound of the general formula wherein -A-, R and R have the meanings set forth above, with a dehydrating agent to form a compound of 2 3 formula I , wherein -A- , R and R have the meanings set forth above and wherein R1 is cyano, or reacting a compound of formula VII 2 3 wherein -A-, R and R have the meaning set forth above, with Ni^OH to form a compound of formula VIII (VIII) wherein -A-, R , and R have the meanings set forth above, and reacting the compound of formula VIII with 5 5 5 R -C0C1 or with (R C0) 0, wherein R is as defined above 1 to form a compound of the general formula I wherein R 5 wherein R is as defined above.

The leaving group, Y, may be any suitable leaving group and, for example, those disclosed in U.S. Patents 4,031,079 or 4,359,420, for example, halogen, alkylthio, e.g., methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0P(0)(0R)2 wherein R is lower-alkyl or -OP( 0 ) ( NR ~ R ~ * ) 2 wherein R* and R* * each represents lower-alkyl or phenyl, or together with the nitrogen atom to which they are attached represent a heterocyclic radical such as morpholino, pyrrolidino, piperidino, or methylpiperazino. The reaction is preferably carried out under alkaline conditions, i.e., in the presence of a base, and among bases alkali metal (e.g., potassium or sodium) alkoxides or hydrides are preferred. The reaction is preferably conducted in the presence of an organic solvent which is nonreactive with the reactants and products of reaction under the conditions of reac-tion, especially an anhydrous solvent and preferably an anhydrous aprotic solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), or the like. The temperature range employed may be any range suitable for the reaction to proceed at a reasonable rate and with-out undue delay or decomposition and a range from a minus forty (-40) degrees Celsius to about room temperature is accordingly usually particularly suitable.

The starting materials employed in the syntheses of the compounds of formula I are either known or may be prepared in conventional manner from commercially available materials, see e.g. J.E. Francis et al., J. Med. Chem. 34, 281 (1991) and references cited therein.

The isocyanomethyloxadiazoles of formula III may be prepared as described in the prior art, e.g. US 4,774,245. 3( 5 ) -Alkyl-5( 3 ) -halomethylisoxazoles, either known or prepared from appropriate starting materials according to known procedures (e.g. U.S. 3,290,301 and Ger. Offen. DE 25 49 962), may by conventional techniques be converted to 3( 5 )-alkyl-5(3 )-aminomethylisoxa-zoles which in turn may be N-formylated and subsequent-ly dehydrated to give isocyanomethylisoxazoles.

The pharmaceutical properties of the compounds of the invention can be illustrated by determining their capability for displacing radioactive labelled flunitraze-pam from benzodiazepine receptors.

The displacement activity of the compounds of the invention may be found by determining the ED5Q value.

The st subs flunitrazepam to benzodiazepine receptors in a living brain to be reduced to 50% of the control value.

Such an in vivo test is carried out as described in US 4,774,245.

Test results obtained by testing some compounds of the invention will appear from the following table I.

TABLE I.

Compound ED50 (mg/kg) 3 0.16 5 0.30 The compound of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one tenth (0.1) milligram of active ingredient or, more broadly, one tenth (0.1) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in poly-hydroxylated castor oil.

Ampoules are convenient unit dosage forms.

For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.

A syrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compounds of the invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutical-ly-acceptable carrier per unit dosage.

A typical tablet which may be prepared by conventional tabletting techniques contains: Active compound 1.0 mg Lactosum 67.8 mg Ph. Eur.

® Avicel 31.4 mg Amberlite® IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph. Eur.

Due to their high degree of affinity for the benzodia-zepin receptors, the compounds of the invention are extremely useful in the treatment of central nervous system ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimination thereof. The important CNS activity of the compounds of the invention includes both anticonvulsant, hypnotic, nootropic and anxiolytic activities along with a low toxicity, together presenting a most favorable therapeutic index. The compounds of the invention may accordingly be administered to a subject, e.g., a living mammal body, including a human, in need of the same for the treatment, alleviation, amelioration, or elimination of an indication, associated with the central nervous system and the socalled benzodiazepine re-ceptors, which requires such psychopharmaceutical treatment, e.g., especially convulsion, insomnia, anxiety and/or dementia states, if desired in the form of a pharmaceuticallyacceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharma-ceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective psychopharmaceutical central nervous system ailment alleviating amount, e.g., an anticonvulsant and/or anxiolytic amount, and in any event an amount which is effective for the alleviation of such a central nervous system ailment due to their benzodiazepine receptor affinity. Suitable dosage ranges are 1-200 milligrams daily, 1-100 milligrams daily, and especially 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

The invention will now be described in further detail with reference to the following examples, which may not be construed as limiting: EXAMPLE 1 5-( 5-cyclopropyl-l, 2, 4-oxadiazol-3-yl )-imidazo[l, 5 1, 2, 4-triazolo[4, 3-c]quinazoline (compound 1) To a stirred slurry of 5-chloro-l, 2, 4-triazolo[4, 3-c]qui-nazoline (3.5 g, 17 mmol) in 40 ml of dry DMF at 10°C was first added 5-cyclopropyl-3-isocyanomethyl-l , 2, 4-oxadiazole (purity 80%, 3.4 g, 18 mmol) and then a solution of potassium tert-butoxide (2.55 g, 23 mmol) in 40 ml of DMF, allowing the temperature to rise to room temperature.

After 1/2 h the mixture was filtered and the filter cake washed with water and finally with ether and dried, giving the title compound as colorless crystals, m.p. 308-314°C.

^H-NMR (CDC13)£: 10.50 (s, 1H, triazolo- ) 8.52 (s, 1H, imidazo), 8.7-7.64 (m, 4H, benzo- ) , 2.45-2.34 (m, 1H, CH), 1.48-1.32 (m, 4H, CH2 ) . MS: m/e 317 (M+), 250, 166 102, 69.

EXAMPLE 2 5-( 5-cyclopropyl-l, 2, 4-oxadiazol-3-yl )-imidazo[l, 5 [1, 2, 4] triazolo[l, 5-c]quinazoline (compound 2) A stirred mixture of crude 5-chloro- [1 , 2 , 4] triazolo[ 1 , 5-c]quinazoline (1.0 g, 4.9 mmol) and 5-cyclopropyl-3-isocyanomethyl-1, 2, 4-oxadiazole (purity 80%, 1.16 g, 6.2 mmol) in 20 ml of dry dimethylformamide (DMF) was cooled to 0°C. Solid potassium tert-butoxide (1.15 g, 10 mmol) was added gradually, keeping the temperature below 5°C, whereafter the mixture was stirred at room temperature for 45 minutes. Then the mixture was stirred at 0°C for 1/2 h and the precipitated product was collected by filtration, rinsed on the filter with water and dried. Yield 0.64 g. An additional amount of product, 0.5 g, precipitated from the mother liqueour by addition of water. The combined crops of crystals was stirred with isopropyl alcohol at 60°C, cooled to room temperature and filtered. The filter cake was dried to give 0.73 g of the title compound m.p. 230-233°C.

^"H-NMR (CDC13) In the same way the following compounds were prepared: 5-(3-cyclopropyl-l, 2, 4-oxadiazol-5-yl )-imidazo[l, 5-a] -[l,2,4]triazolo[l, 5-c]quinazoline, m.p. 267-269°C, 1H- MR (CFgCOOD) cT : 9.68 (s, 1H), 9.09 (s, 1H), 8.88- 8.02 (m, 4H), 2.50-2.28 (m, 1H), 163-1.2 (m, 4H); prepared from 5-chloro-[l, 2, 4] triazolo[ 1 , 5-c] quinazoline and 3-cyclopropyl-5-isocyanomethyl-l, 2, 4-oxadiazole. ( compound 3 ) 5-( 5-cyclopropyl-l , 2, 4-oxadiazol-3-yl )-2-methyl-imi-dazo[l , 5-a] [1 , 2, 4] triazolo[l, 5-c] quinazoline, m.p. 280-283°C, MS: m/e 332 (M++l), 331, 264, 129, 102, 69; prepared from 5-chloro-2-methyl- [1, 2, 4] triazolo[l, 5-c] quinazoline and 5-cyclopropyl-3-isocyanomethyl-l, 2, 4-oxadiazole. (compound 4) 12-chloro-5- ( 3-cyclopropyl-l , 2 , 4-oxadiazol-5-yl ) -imidazo[l, 5-a] [1,2,4] triazolo[l, 5-c] quinazoline, m.p. 278-284°C, MS: m/e 351/353 (M+/M+ +2), 270/272, 268, 163; prepared from 5, 10-dichloro- [1, 2, 4] triazolo[ 1 , 5-c]quinazoline and 3-cyclopropyl-5-isocyanomethyl-l, 2, 4-oxadiazole. (compound 5) 12-chloro-5- ( 5-cyclopropyl-l, 2, 4-oxadiazol-3-yl )-imidazo[l, 5-a] [1,2, 4] triazolo[l, 5-c] quinazoline, m.p. 262-263°C, MS: m/e 351/353 (M+/M+ +2), 268, 229, 200, 163, 136, 100, 69; prepared from 5, 10-dichloro-[1, 2, 4] triazolo[l, 5-c] quinazoline and 5-cyclopropyl-3-isocyanomethyl-1, 2, 4-oxadiazole. (compound 6) 5- ( 3-cyclopropyl-l , 2, 4-oxadiazol-5-yl )-ll-methyl-imidazo[l, 5-a] [1, 2,4]triazolo[l, 5-c]quinazoline, m.p. 271-273°C, MS: m/e 331 (M+), 250, 248, 222, 209, 143, 116, 89, 53; prepared from 5-chloro-9-methyl- [1, 2, 4] triazolo[l, 5-c] quinazoline and 3-cyclopropyl-5-isocyanomethyl-1, 2, 4-oxadiazole. (compound 7) 5-( 5-cyclopropyl-l, 2, 4-oxadiazol-3-yl )-ll-methyl-imidazo[ 1, 5-a] [1, 2, 4] triazolo[l , 5-c]quinazoline, m.p. 280-282°C, MS: m/e 331 (M+), 264, 248, 209, 181, 143, 116, 89, 69; prepared from 5-chloro-9-methyl- [1, 2, 4] triazolo [ 1 , 5-c] quinazoline and 5-cyclopropyl-3-isocyanomethyl-1, 2, 4-oxadiazole. (compound 8) 5-( 5-methyl-l, 2, 4-oxadiazol-3-yl )-12-methyl-imidazo[l, 5-a] [1, 2, 4] triazolo[l, 5-c] quinazoline, m.p. 265-269°C, MS: m/e 305 (m+), 263, 210, 184, 181, 157, 89, 43; prepared from 5-chloro-10-methyl-[1, 2, 4] triazolo[ 1 , 5-a] quinazoline and 3-isocyanomethyl-5-methyl-l, 2, 4-oxadiazole. (Compound 9) 5-( 5-cyclopropyl-l, 2 , 4-oxadiazol-3-yl ) -12-methyl-imi-dazo[l , 5-a] [1, 2, 4] triazolo[ 1 , 5-c] quinazoline, m.p. 254-256°C, MS: m/e 331 (M+), 263, 69; prepared from 5-chloro-lO-methyl- [1,2, 4] triazolo [ 1 , 5-a] quinazoline and 5-cyclopropyl-3-isocyanomethyl-l, 2, 4-oxadiazole. (compound 10) 12-chloro-5-( 5-cyclopropyl-l, 2 , 4-oxadiazol-3-yl ) -2-methyl-imidazo[l, 5-a] [1,2, 4] triazolo[l, 5-c] quinazoline, m.p. 210-213, MS: m/e 365, 298, 69; prepared from 5,10-dichloro-2-methyl- [1,2,4] triazolo[ 1 , 5-c] quinazoline and 5-cyclopropyl-3-isocyanomethyl-l , 2, 4-oxadiazole. ( Compound 11 ) 14

Claims (4)

1. CLAIMS Tetracyclic imidazotriazoloquinazoline compounds having the formula I : wherein A together with the o<, -marked carbon atom and the β-marked nitrogen atom is one of the groups R wherein R is hydrogen, trifluoromethyl, or and 2 3 4 R , R and R independently are hydrogen, hydroxy, halogen, CN, C2_g-alkenyl , C2_g-alkynyl, trifluoromethyl, C1_g-alkoxy, dialkylaminoalkoxy, aral-koxy, aryloxy which may be substituted with halogen or 6 7 6 alkoxy, a cyclic amino group, or NR R , wherein R and 7 R independently are hydrogen or C^^-alkyl, and pharma- 101046/2 15 ceutically acceptable acid addition salts thereof.

2. A compound which is 5-( 5-cyclopropyl-l , 2, 4-oxadia- zol-3-yl )-imidazo[l, 5-a] [1,2, 4] triazolo[ 1 , 5-c]quinazo- line.

3. A compound which is 5-(3-cyclopropyl-l,2,4-oxadia- zol-5-yl )-imidazo[l, 5-a] [1, 2, 4] triazolo[l, 5-c]quinazo- line.

4. A compound which is 12-chloro-5-(3-cyclopropyl- 1, 2, 4-oxadiazol-5-yl ) -imidazo[l, 5-a] [1,2,4] triazolo- [ 1 , 5-c] quinazoline . 5_^ A compound which is 12-chloro-5- ( 5-cyclopropyl- 1, 2, 4-oxadiazol-3-yl )-imidazo[l, 5-a] [1,2, 4] triazolo- [ 1 , 5-c] quinazoline . 6. A pharmaceutical composition comprising as active component an imidazotriazolbquinazoline compound according to claims 1-5 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically-acceptable carrier or diluent. A pharmaceutical composition suitable for use in the treatment of a central nervous system ailment comprising an amount of a compound according to claims 1-5 which is effective for the alleviation of such disorder together with a pharmaceutically-acceptable carrier or diluent. 8. A pharmaceutical composition according to claim 6 or 7 wherein it is in the form af an oral dosage unit containing 0.1-100 mg of the active compound. 9. A method of treating a central nervous system ailment in a non-human subject in need of such treatment com- 101046/2 16 prising the step of administering to said subject an amount of a compound accordin to Claims 1-5 which is effective for the alleviation of such ailment. 10. A method of treating a central nervous system ailment in a non-human subject in need of such treatment comprising the step of administering to said subject an amount of a compound according to Claims 1-5 which is effective for the alleviation of such ailment in the form af a pharmaceutical composition thereof, in which it is present together with a pharmaceutically acceptable carrier or diluent. 11. A method of preparing a compound according to claims 1-5, CHARACTERIZED in a) reacting a compound of formula II wherein A, R and R are as defined above and wherein Y is a leaving group, with a compound having the formula III CN - CH2 - R1 (III) wherein R^ is as defined above, to form a compound of the general formula I, or b) reacting a reactive derivative of a compound having the general formula IV wherein A, R and R are as defined above with a compound having the general formula V R5-C( =N0H)NH2 (V) wherein R is as defined above to form a compound of the general formula I wherein R^ is 5 wherein R is as defined above, or c) reacting a compound of the general formula VI wherein -A-, R and R have the meanings set forth above, with a dehydrating agent to form a compound of 101046/2 18 formula I, wherein -A-, R and R have the meanings set forth above and wherein R1 is cyano, or d) reacting a compound of formula VII wherein -A-, R , and R have the meaning set forth above, with NH.-0H to form a compound of formula VIII wherein -A-, R , and R have the meanings set forth above, and reacting the compound of formula VIII with 5 5 5 R -C0C1 or with (R CO^O, wherein R is as defined above to form a compound of the general formula I wherein R is wherein R is as defined above. 12. Use of a compound according to claims 1-5 for producing a pharmaceutical composition for the treatment of an indication related to a central nervous system ailment substantially as described in the specification. For the Applicants DR. RE |I^NWb^fcsLC_OHLN A_ND PARTNERS ay: 18 formula I, wherein -A-, R and R have the meanings set forth above and wherein R is cyano, or d) reacting a compound of formula VII wherein -A-, R , and R have the meaning set forth above, with NH 0H to form a compound of formula VIII wherein -A-, R , and R have the meanings set forth above, and reacting the compound of formula VIII with 5 5 5 R -C0C1 or with (R C0)20, wherein R is as defined above to form a compound of the general formula I wherein R is wherein R is as defined above. 12. Use of a compound according to claims 1-5 for producing a pharmaceutical composition for the treatment of an indication related to a central nervous system ailment. For fne Applicants ÷~ DR. REINUjERD 60HN AND PARTNERS By* / / . 7